Biomaterials in Ophthalmology What are biomaterials? Biomaterials are synthetic polymers or modified biopolymers, as well as metals, glasses, and ceramics used for implants or other medical devices. What are Uses of biomaterials In ophthalmology ? 1 - intraocular lenses (IOL) 2 - implants for retinal detachment surgery, vitreous replacements that are widely used. 3 - drainage implants in terminal glaucoma 4 - keratoprosthesis, and those used in ophthalmic plastic surgery 5 - artificial tears Many important requirements must be met by ophthalmic biomaterials, including the ability to deliver oxygen to tissues, refractive changes, tissue protection during surgery, tissue integration and healing modulation History: Onofrio Abbate, in 1862, implanted a foreign material for a biomaterial. It was a glass disc enclosed in a two - ring skirt forming an artificial cornea. This device was tested on the cornea of animals, but it was unable to stay in place for more than a week. Later, Dimmer attempted to construct an artificia l cornea composed of celluloid implanting it in four human patients; however, it was rejected in the first few months. Then fully synthetic polymer was used as an implantable ophthalmic biomaterial composed of polyvinyl alcohol (PVA) gel. It was followed by the first artificial cornea made from polymethyl methacrylate (PMMA) A few years later, a synthetic polymer, poly(1 - vinyl - 2 - pyrrolidone), was implanted in the vitreous cavity as a vitreous substitute. It was mainly thanks to the introduction of synthetic hydrogels that the range of biomaterials to treat ophthalmic lesions developed Innovations were made to improve quality standards, to reduce costs and provide better accessibility. One of the primary challenges in ophthalmic biomaterials is achieving optimal biocompatibility, ensuring that the material does not cause tissue rejection when in contact with ocular tissues & they support normal physiological functions. Mechanical properties play a crucial role in the performance of ophthalmic biomaterials, particularly in applications such as corneal implants and intraocular lenses The material must possess sufficient strength and flexibility to withstand the mechanical stresses within the eye, including the constant movement of the eyelids and the pressure exerted by intraocular fluids. At the same time, the material should maintain its structural integrity over time to ensure long - term stability and functionality Optical properties are another key consideration in ophthalmic biomaterials, particularly for devices that affect vision, such as intraocular lenses and corneal implants. The y must possess optical clarity and transparency to allow for the passage of light, thereby preserving visual acuity and minimizing potential side effects such as glare or halos. Proper sterilization methods must be employed to eliminate microbial contamination while preserving the integrity of the material’s properties. Additionally, appropriate packaging is necessary to protect the biomaterial from environmental factors Many important requirements must be met by ophthalmic biomaterials, including the ability to deliver oxygen to tissues , refractive changes, tissue protection during surgery, tissue integration and healing modulation Artificial Tears Lacrimal Film Composition The tear film is a trilaminar structure composed of a lipid layer of about 0.1 μm, a 71 μm thick aqueous layer and finally the mucin layer which is 0.02 – 0.05 μm thick .The lipid layer is secreted by the meibomian glands. It delays the evaporation of the aqueous layer & reduces the tension surface of the tear film, thereby preventing tears from spreading on the cheeks so Lipids play a critical role in tear film stabilization. The watery layer is secreted by the lacrimal glands provides access for atmospheric oxygen to the avascular corneal epithelium, antibacterial protection, a smooth surface for optimal vision and removes debris from the cornea and conjunctival sac. The mucin layer is secreted by conjunctival goblet cells and covers the ocular surface allows the film tear acts as a lubricant for eyelid movement on the ocular surface , protects the cornea during blinking and reduces the hydrophobia of epithelial cells Do you know what mean od dry eye &its mechanism of action? Dry eye is defined as a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis and accompanied by o cular symptoms of discomfort, watering & blurring of vision. It is affecting millions of people worldwide, with varying degrees in severity ranging from simple discomfor t to pain or fluctuating vision. Aetiologias of DED are often classified as : 1 - environmental as in air conditioning rooms, hot humid atmosphere , computer use for long time without blinking 2 - aqueous tear deficient due to disease of lacrimal gland A problem in lipid secretion, mucins or water or an increase in tear film evaporation can cause a DED, which often has a multifactorial origin. DED is usually triggered by the environment, be a side effect of a drug and it s prevalence increases with age . DED can be episodic or chronic. Patients often complain of eye irritation and occasional blurred vision, but if patients with chronic DED are not treated, symptoms may persist and cause eye damage without impair ing vision The treatment of DED reduces symptoms and prevents eye damage; furthermore, artificial tears are the most used treatment for this condition, regardless of disease severity Formulation of Tear Substitutes The term artificial tears mainly refer to products sold without medical prescription, whose purpose is to replace and/or supplement the natural tear film. Tear substitutes include a variety of products to target one or more layers of the tear film and have similar compositions. Main action of artificial tears: Artificial tears must have several short - term benefits, improve eye lubrication, decrease tear film evaporation, have a good retention time and should not change the eye optics. The goal is to prevent corneal damage and alleviate symptoms with few side effects. The aqueous base is the more abundant component. To improve its lubrication time and retention on the ocular surface, several viscosity imp rovers are usually incorporated What is usual forms of artificial tear &its composition : Each artificial tear varies in terms of composition, viscosity, duration of action, presence or absence of preservative, osmolarity and pH, although they generally have a pH of 6.5 to 7.5, close to the pH of human tears Conventional ophthalmic dosage forms such as eye drops (formulated as solutions or suspensions), gels and ointments are preferred for administering drugs to the ocular surface. Its relative ease of use, non - invasiveness, low cost of production and its ease of manufacture offer undeniable advantages. However, the ocular aqueous solutions experience a very short contact time with the ocular surface, due to rapid nasolacrimal drain age, resulting in low ocular bioavailability Ointments are formulated with a specific blend of mineral oil and petroleum. In general, ointments do not promote bacterial growth and therefore do not require preservatives but are not well tolerated by patients with severe dry ey e it can be used for prolonged action, especially during eye surgery or during night applications. The change in the refractive index between the tear film and ointment causes blurred vision, which is one of the main disadvantages Gels containing cross - linked high - weight molecular acrylic - acid polymers, have longer retention times than artificial tear solutions, have a lower visual staining effect than ointments , During its use, vision is initially blurred, but the phenomenon disappears quickly Viscosity - improving agents include, carboxymethyl cellulose (CMC), hyaluronic acid (HA), hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP), They can increase the time of permanence in the eye due to their mucoadhesive properties HPMC and PVA are widely used in artificial tears, although they have a short duration of action. Viscosity agents make it possible to increase the tear film thickness, improve tear retention to the surface and protection of the ocular surface, decrease drying and help maintain physiological corneal thickness Benzalkonium chloride (BAC) is the most used preservative in eye drops. It causes eye irritation, is responsible for significant toxicity to the surface of the eye and cornea and aggravates dry eye in particular if artificial tears are used more than 4 times a day. Other preservatives may c ause less irritation, such as sodium chlorite . So perseverative free tear substitutes preferred, The lipid layer of the tear film plays an important role in preventing the evaporation of tears. A variety of oils have been incorporated into the formulations of eye lubricant to help restore the lipid layer of the tear film. Drops containing lipids a re formulated as emulsions, but pressure is required to overcome the effects of surface tension. The types of lipids used include phospholipids, saturated and unsaturated fatty acids, and triglycerides. It also includes mineral oil in various concentrations, castor oil, olive oil, coconut oil, soy oil and lecithin, in combination with various emulsifying agents and surfactants Contact Lenses ( CL) The use of contact lenses has expanded enormousl y because of the development of new materi als with improved physiological prop erties compared to the original ( poly methyl methacrylate) (PMMA). Types of contact lens : 1 - Soft contact lenses are used by 85% of contact lens wearers; the rest use 2 - rigid lenses The rigid contact lenses can be divided in two main groups: non oxygen - permeable poly(met hyl methacrylate) (PMMA) l enses and oxyge n permeable lenses. Wh ich material used for manufacture CL ? 1 - PMMA lenses have been used fo r approximately half a century. This polymer more recently has been replaced by pol ymers with higher oxygen permeability (Dk) PMMA h as very good optical qualities , is light weight, and is easily manufactured and well tolerated The major drawback with the use of this m aterial in CL' s manufacture is the low oxygen permeability. PMMA lenses are small in diameter and float on the thin layer of preco rn eal tear film that is continuously exchanged with blinking and lens movements to permit corneal oxygenation. 2 - Cellu lose acetate butyrate (CAB ) was among the ea rly gas - permeable CL materials. CAB is a modified polysaccharide derived from a natur al polymer, cellulose. Compared to PMMA, CAB is softer and more easily distorted by water absorption. Therefore, t hese lenses tend to warp and scratch easily The develo pment of new materials made the CAB CLs obsolete. The lo w Dk of the first rigid CLs was improved by copolymerization of methyl methacrylate with different amounts of 3 - siloxanylalkyl methacrylate (SM) monomers. Hardness and lens stability are modulated by varying the amount of methyl methacrylate and of a cross linking agent, such as ethylene glycol dimethacrylate, in the polymer formulation. To improve the wettability of CLs, methacrylic acid is used in most formulations. Rigid gas - permeable CLs float on the thin layer of the precorneal tear film that is continuously exchanged with bl inking and lens movement to perm it corneal oxygenation. T he siloxanyl component gives SM copolymers good oxygen permeability. A further development in this field was the addition of a 4 - pe rfluorinated alkyl methacrylate monomer in the fo rmulation of the SM mate rials. The fluorosiloxanylalkyl methacrylate (FSM) copolymers resulted in lenses with improved mechanical properties and enhanced Dk . The fluoromonomers, increase oxygen permeabilit y of these lenses because of the ability of fluorine to d issolve oxygen. Because of the low surface energy of the perfluorinated m aterials , these lenses have increased resistance to soiling, The importance of 5 - silicone polymers in CLs is related to their high oxygen permeability. Silicone rubb er is a well - known material for soft CLs, particularly for the correction of aphakia in children. Some rigid sil icone lenses also are available The main downside to the use of silicone in CLs is 1) its hydrophobicity . The surface of silicone lenses can be treated to improve wettability, but these treatments are not always long - lasting. Moreover, the silicone lenses develop 2) deposits of mucous and proteins quite easily . In addition, the major complication of silicone rubber lenses is 3) adherence to the cornea. Contrasting with the good tear exchange over the cornea obtained with rigid CLs, tear exchange under hydrogel CLs is poor. Therefore, to reach the cornea, the oxygen from the air or from the palpebral conjunctiva must permeate through the lenses. The original hydrogel CLs providing 3 8% hydration were made of poly(2 hydroxyethyl methacrylate) (PHEMA) Because the Dk increases with water content, new hydrogel lenses made 6 - of hydroxyethyl methacrylate (HEMA) copolymers with monomers of higher hydrophilicity, such a as methacrylic acid and vinyl pyrrol idone, were developed. To obtain higher oxygen transmissibility (Dk/L, where L is the lens thickness) the ideal hydrogel CL is an ultrathin, high hydration lens. Table 1. Advantages and disadvantages of the most commonly used contact lens biomaterials. Biomaterial Disadvantages Advantages Poly( vinyl alcohol) (PVA) Low permeability to oxygen; fixed water contact Low cost; biocompatible; easy manufacturing Silicon hydrogel Expensive; abrasive behavior High permeability to oxygen; high durability Biomaterial Disadvantages Advantages Hydroxy ethyl methacrylate (HEMA) hydrogel Low permeability to oxygen; protein deposition problems Low cost; biocompatible; several copolymer possibilities Polymethyl methacrylate (PMMA) Impermeable to oxygen; not flexible in the eyes; abrasive behavior Low cost; well - studied polymer How to clean CL ? :: Multipurpose solutions (MPS) are the most used lens care systems today; they do not require other components in the lens care process once they combine cleaning, washing and disinfection in a single product MPS usually contain polyhexanide, being active against a wide range of bacteria, has a higher molecular weight than chlorhexidine, therefore it cannot penetrate the lens matrix decreasing the likelihood of potential toxic reactions or hypersensitivity.. Nowadays, MPS products usually use two disinfectants instead of one, with the process being called double disinfection Contact lenses are nowadays also seen as a tool for ophthalmic treatments that require the delivery of a drug to the eye. Eye drops have a low bioavailability of common ophthalmic treatments; therefore, new lenses are being developed based on drug delivery materials Keratoprosthesis What is Keratoprosthesis & its uses: Corneal prostheses, also known as artificial corneas or keratoprostheses, are innovative devices that are designed to restore vision in individuals with corneal blindness or irreparable corneal damage When a corneal transplant cannot be performed or has failed repeatedly, a keratoprosthesis represents the only hope for vision. Biomaterials play a crucial role in the development and fabrication of corneal prostheses by providing biocompatible scaffolds that mimic the structure and function of the natural cornea ( How to manu f acture Keratoprosthesis ?? Most keratoprosthesis (Fig.) consist of an optical cylinder of PMMA that penetrates the opaque tissue and some skirt or plates to secure the prosthesis to the tissue . This skirt may be of different materials, such as metal (gold, platinum, tantalium, titanium), ceramic, silicone and other polymers, textile, or biological material (dentin, bone, cartilage). A keratoprosthesis is not a biologically integrated device and a frequent complica tion following implantation is extrusion , a problem that is common to all implants It is very difficult to obtain a good adherence bet ween the implant and the living eye tissu es and frequently ulceration at the exposed ju nctions occurs. This may result in infections and epithelial downgrowth Since the proliferation of epithelial cells is no longer inhibited by cell - to - cell contact and microscopic empty spaces are left around the impl ant, retro implant proliferation with extrusion of the prosthesis, leakage of aqueous humor, and infection No keratop rosthesis has been consistently successful in a large number of patients for long follow - up periods. Various implants and tech niques are still experimental in patients with an opaque cornea and poor prognosis for corneal transplant. The Strampelli' s osteo - odonto - keratoprosthesis (OKP) and the Cardona's keratoprosthesis may represent valid options. In the OKP, the PMMA opt ic is fixed with acrylic cemen t to the lamellar section of an autologous or homologous tooth. The insertion of the muc osal epithelium on the alveolar dental liga ment accounts for the long - term retention of the prosthesis. The temporary keratoprosthesis is made of a cylinder of PMMA that is positioned in a trephined corneal bed. It can be used only in aphakic eyes since the crystalli ne lens would be damaged by the prosthesis. On completion of the vitreoretinal procedure, the prosthesis is replaced by a corneal graft Corneal implants The other important group of corneal implants are the intracorneal ones , used to alter the d ioptric power of the eye Since nutrition of t he anterior layer of the cornea depends largel y on metabolites diffusing from the anterior chamber, inserting impermeable implants, such as PMMA or polysulfone, in the stroma results in corneas opaci ties, ulceration, and implant extrusion For this reason, the in tracorneal implants most likely to succeed are those made of hydrogel materials Since hydrogels have low refractive index, to achi eve the optical correction, the intracorneal implant mu st change the corneal curvature. P otential advantages of hydrogel intracorneal i mplants include the possibility of sterilizat ion, precise manufacturing, and easy availability. Finally, a rece nt development in intracorneal. implants are the intrastromal rings that change the radius of corneal curvature and hence the refractive power of the eye. These implan ts are made of PMMA or silicone rubber. They are implanted with minimal surgical trauma that does not involve the center of the cornea and should not interfere with the corneal metabolism Corneal Transplants What is corneal transplant &how biomaterials play role?? Corneal transplantation, also known as corneal grafting, is a surgical procedure performed to replace a damaged or diseased cornea with healthy donor tissue Biomaterials play a crucial role in corneal transplants by serving as scaffolds for tissue engineering, providing structural support, and promoting tissue integration and regeneration. Traditional corneal transplants involve the transplantation of full - thickness donor corneas, known as penetrating keratoplasty (PK ), which requires the removal of the entire diseased cornea and replacement with donor tissue. While effective, PK is associated with significant risks and complications, including graft rejection, infection, and astigmatism to address the limitations of traditional corneal transplantation, researchers have developed innovative biomaterial - based approaches for corneal repair and regeneration . One such approach is lamellar keratoplasty , which involves the selective replacement of damaged corneal layers with donor tissue. This technique preserves the healthy endothelial layer of the recipient cornea, reducing the risk of endothelial rejection and improving long - term graft survival Lamellar keratoplasty can be further refined using biomaterials such as synthetic polymers and hydrogels to create customized scaffolds that mimic the structure and function of the corneal stroma , promoting tissue integration and wound healing How biomedical engineering help to increase success of keratoplasty: In recent years, advances in tissue engineering and regenerative medicine have led to the d evelopment of bioengineered corneal substitutes that offer potential alternatives to traditional donor corneas . These bioengineered constructs are typically composed of biocompatible and biodegradable materials, such as collagen - based scaffolds, seeded with corneal cells derived from the patient’s own tissues or from allogeneic sources. Biomaterials play a crucial role in enhancing the safety and efficacy of corneal transplants by providing platforms or drug delivery and immunomodulation. Localized drug delivery systems incorporated into biomaterial scaffolds can release therapeutic agents such as corticosteroids, immunosuppressants, or growth factors directly into the corneal tissue, reducing inflammation, preventing graft rejection, and promoting tissue healing , reducing the risk of graft rejection and improving graft survival rates Intraocular Lenses Intraocular lenses (IOLs) consist of an optical portion and haptics to hold the implant in plac e. The first IOLs, of pure PMMA were implanted in the posterior chamber of the eye. They were bi convex lenses with a peripheral notch for manipula tion. Because of the relatively large size (diameter 8.3 mm, central thickness 2.4 mm), weight, and poor finish of the IOLs, there was a h igh incidence of complications, part icularly dislocations, ischemic iris atrophy, and chronic uveitis. Anterio r chamber lenses have been used since 1952, but they resulted in many inst ances of corneal swelling owing to endothelium touch. kinds of iris - f ixated IOLs have been designed, Corneal and uv eal related complications still occurred and dislocation problems could not be avoided. Materials used in manfacture of IOL : The improved design and manufacture of I OLs, the quality of the surgical techniques, and the advent of viscoelastic substances had a very important role in determining the current high success rate of IOL implantations. 1) PMMA is the material used for most IOLs. Thes e can be one - piece PMMA or have haptics ma de of another material, usually polypropylene. injection molding are the most common manufacturing techniques for these lenses. A lower - mol - wt, lower viscosity non crosslinked PMM A is used in the manufacture of injection - mo lded IOLs. Cleaning, polishing, inspection, and st erilization are other important steps in the manufacturing process of IOLs that will determine biocompatibility Drawbacks of PMMA IOL &HOW TO reduce them ? For at le ast 40 yr PMMA has proven to be a good material for IOLs, but it is not the ideal one. The relative hydrophobicity of this polymer can result in endothelial cell loss by lens touch Because of its hardness, uveal contact with the IOL can cause chronic inflam mation. Moreover, PMMA supports membrane fo rmation and cellular adherence. One of th ese processes keeps the surface hydro phobic and claims to remove all molecular irregularities to create an alm ost absolutely smoot h surface that resists cellular adherence. Another procedure con sists of making the IOL surface highly h ydrophilic by permanent binding of heparin. In vitro studies have shown that heparin - coat ed lenses were characterized by less platelet a dhesion, macrophage deposition, and granulocyte activation than conventional PMMA lenses Current s urgical techniques, focusing on more rapid v isual rehabilitation and on the reduction of postoperative residual astigmatism (small in cision, scleral tunnels, suture reduction), have encouraged the development of foldable lenses. Since PMMA is not foldable, IOLs made of this material cannot be used with a 3 - mm incision cataract surg ery. 2 - Silicone ru bber is one of the new foldable IOL material s. Silicone rubber, contrary to PMMA, is autoclavable. Its refractive index, is cl ose to that of the normal human lens. Studies suggest that silicone lenses might have less light - backscatte ring compared to PMMA lenses 3 - Hyd rogel IOLs are made of the same PHEMA or similar materials as the hydrogel CLs, and are presumed to be less damaging to the corneal endothelium They also produce a lower inflammatory response when compared to PMMA lenses. Also, PHEMA lenses have better Y AG la ser compatibility than the PMMA lenses. Howe ver, the average performance on contrast sensi tivity testing in patients with PMMA lenses wa s significantly better compared to patients with PHEMA lenses. The human e ye without the crystalline lens has poor filt ration of radiations, therefore ultra violet light absorbers are used in IOLs to cut off these radiations that could be harmful to the posterior segment of eye present, In PMMA lenses, these UV absorbers can be physically blended or chemically bonded to the polymer eye. Viscoelastic Substances Normal composition of vitreous & its role in its action : T he vitreous body, also called the vitreous or vitreous humor, fills the posterior space of the eye, between the lens and the retina. It occupies more than two thirds of the eye volume. It is a clear gel, highly transparent, inhomogeneous and consists of se veral parts with different densities and biochemical compositions The vitreous is composed of water, proteins (mainly collagen), GAG (hyaluronic acid, chondroitin